Apoptosis plays a central role in the development and homeostasis of all multi-cellular organisms. Abnormal inhibition of apoptosis is a hallmark of cancer and autoimmune diseases, whereas excessive activation of cell death is implicated in neuro-degenerative disorders such as Alzheimer's disease. Pro-apoptotic chemotherapeutic drugs provide a recent approach to overcoming the clinical problem of drug resistance; see, e.g. Makin et al., Cell Tissue Res. (July 2000) 301(1):143-152 (“Apoptosis and cancer chemotherapy”).
The mechanism of apoptosis is conserved across species and executed with a cascade of sequential activation of proteases called caspases. Once activated, these caspases are responsible for proteolytic cleavage of a broad spectrum of cellular targets that ultimately lead to cell death. IAPs (inhibitor-of-apoptosis proteins) are a family of proteins that regulate apoptosis by inhibiting caspases. The viral and cellular IAPs contain one to three N-terminal baculovirus IAP repeat (BIR) motifs and a C-terminal RING finger domain. Examples of human IAPs include the X-linked IAP (XIAP), cIAP2 (also referred to as HIAP1 or BIRC3) and cIAP1 (also referred to as HIAP2 or BIRC2).
A mitochondrial protein called Smac (‘second mitochondria-derived activator of caspases’) has been shown to bind to and inhibit a wide variety of IAPs, thereby promoting caspase activation, and is believed to be a key regulator of apoptosis in mammals. See Du, et al., Cell (2000) 102:33-43; Verhagen et al., Cell (2000) 102:43-53; and Vucic et al., Biochem. J. (2005) 385(1):11-20. N-terminal Smac-derived peptides and mimetics have been shown to similarly inhibit IAPs, and promote caspase activation. IAPs are components of TNFR (tumor necrosis factor receptor), so IAP inhibitors can divert TNFR signaling from an NfkB-mediated pro-inflammatory signal, to an anti-inflammatory apoptotic signal.
Defective apoptosis regulation can confer resistance to many current treatment protocols, leading to tumor growth. This may occur as a result of overexpression of IAPs, which inhibit the caspases that would otherwise initiate apoptosis. Alternatively, deregulation can occur as a result of underproduction of the Smac peptides that act to inhibit IAP activity. Thus, a deficiency of Smac can allow IAP to prevent apoptosis from occurring when it should. A Smac mimetic, such as the compounds of the present invention, can replace the activity of Smac and thus promote desired apoptosis.
Debatin, et al., WO 03/086470, describes Smac-peptides as therapeutic agents useful against cancer and autoimmune diseases; they are reported to act by sensitizing the cells toward TRAIL-induced or anticancer drug-induced apoptosis. (TRAIL stands for TNF related apoptosis-inducing ligand). See also Li, et al., Science (3 Sep. 2004) 305:1471-14744. Debatin provides in vivo evidence that Smac induces the eradication of certain tumors such as glioblastoma tumor models in animals when administered in combination with TRAIL. According to Debatin, aggressive cancer phenotypes, which result from deregulation of signaling pathways, commonly fail to undergo apoptosis when they otherwise would, allowing rapid and abnormal tissue growth. Bockbrader, et al., disclose efficacy of Smac mimic compounds on breast cancer cell lines when used in conjunction with TRAIL or etoposide, or when used in cells that express TRAIL at relatively high levels. Oncogene (2005) 24:7381-7388.
Similarly, according to Debatin, defects in apoptosis regulation play a key role in the pathogenesis of autoimmune disorders, including lupus erythematodes disseminatus and rheumatoid arthritis. Accordingly, compounds that mimic the activity of Smac can treat some of the effects of such conditions.
Dimeric compounds have been disclosed in U.S. Pat. No. 7,309,792 and U.S. Patent Applications US 2008/0119532, US 2008/0051389 and US 2009/0104151. The compounds have two binding domains linked by a linker that is broadly described. Dimeric Smac inhibitors have also been disclosed in U.S. Pat. Nos. 7,547,724, 7,579,320, 7,589,118, and U.S. Patent Applications US 2007/0093429, US 2007/0219140, and US 2009/0192140. Another U.S. Patent Application, US 2006/0025347, describes small molecule compounds having activity related to promotion of apoptosis. However, while the latter reference mentions that dimeric compounds can be used, none of the compounds it discloses have a dimeric structure.
Several recent patent applications, for example, US 2006/0025347, US 2005/0197403, WO 2006/069063, US 2006/0014700, WO 2005/094818, and WO 2005/097791, each of which is incorporated herein by reference in its entirety, disclose monomeric IAP inhibitors, but do not describe dimeric structures.